802
JOHN WEIJLARD,
MAX TISHLER AND A:E. ERICKSON
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p-Methyl-p-( 2,4-dimethyl-3-chloro-6-methoxypheayl) acrylic Acid (V); Brucine Salt.-A solution of 3 g. of the acrylic acid (V) and 4.63 g. of anhydrous brucine in absolute ethanol was warmed on -the steam-bath. Following removal of the solvent, 50 cc. of absolute ether was added and the viscous material triturated until a fine powder wa: formed. A sample of 3 g. of this product, m. p. 115-126 (cor.), was refluxed with 400 cc. of absolute ether and filtered from a small amount of brucine. The solution was kept a t 0' for twenty-four hours, whereupon an additional 0.5 g. of brucine was obtained. The solution was filtered, concentrated, seeded, and within forty-eight hours 0.5 g. of the brucine salt, m. p. 132-134O (cor.), was obtained. The salt was analyzed without further crystallization since Fresh solvent was found t o deconipose the salt causing brucine to precipitate. Further low-melting 'crops could be obtained on concentration of the mother liquors. Anal. Calcd. for C1JHlsC103.CaaHlcrN40~:C, Gti.C$l; H, 6.37; K, 4.31. Fottnd: C, 66.76; H, 6.13; N, 14+. Rolalton. 0 1 g. made up to 5 cc. with absolute ethanol KO mutarotna t 22' gave CXD -0 55; I , I , [ , ] ~ Z D -22'. tion was observed after seventeen hours. Decomposition of all salt fractions with cold aqueous hydrochloric acid gave only inactive acids. &Methyl-,+( 2,4-dimethyMCmethoxyphenyl)-N-acrylylglycine (XII); Brucine Salt.-A solution of 0.7 g. of 8methyl @ - (2,4 - dimethyl - 6 methoxyphenyl) - S - acrylylglycine (XII) and 1 g. of anhydrous brucine in 10 cc. of absolute ethanol was warmed on the steam-bath, then transferred t o a breaker and the solvent removed in a vacuum desiccator over calcium chloride a t room terperature. On digesting the oily residue with absolute ether, a %bite powder readily formed, ni. p. 152-155' (cor.). The substance was instantaneously soluble in water. On refluxing 1 g. of the crude salt with 600 cc. of absolute ether all went into solution leaving merely a trace of an amorphous solid. Following filtratioii the solution was concentrated by spontaneous evaporation. After five days the volume had decreased t o 200 cc. and 0 45 g. of a white crystalline solid, m. p. 158' (cor ), was obtained (Fraction A). Further concentratiun to 25 cc. gave 0.2 g. (Fraction B). The residue after complete evaporation was an oily solid. A n d Calcd. for CioHieNO,.CnrH~sNzOc: C, 67.93; H, 6.75; N,6.25. Found: C, 67.71; H,6.64; N,6.36. Rotation. Fraction A. 0.1 g. made up t o 5 cc. with absolute ethanol at 27' gave a~ -0.232; /, 1; [alnO -11.6O.. After twelve and a half hours no evidence of mutarotation was observed
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[CONTRIBUTIOX FROM
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Attempts to liberate the free glycine with cold aqueous hydrochloric acid gave merely oil? Attempted Resolution of Other Acrylic Acids.-& Methyl - B (2,4 - dimethyl - (5 - methoxyphenyl) - acrylic acid (IV) and a,@-dimethyl-~-(2,4-dimethy1-3-nitro-6methoxypheny1)-acrylic acid (IX) could not be induced to give crystalline alkaloidal salts by the prgedures previously described.
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Summary 1. 4,5,7-Trimethylcoumarin, prepared from 3,5-dimethylphenol and ethyl acetoacetate, and its Gnitro and. 6-chloro derivatives were hydrolyzed with alkali and methylated to p-methyl-& (2,4-dimethyl-6-methoxyphenyl)-acrylicacid, .pmethyl-@-(2,4-dimethyl-3-nitro- G-methoxypheny1)-acrylic acid and P-methyl-P-(2,4-dimethyl-3chloro-6-methoxyphenyl)-acrylicacid. 2. 3,.i,5,'i-Tetrdmethy1coumarin, prepaxed from 3,5-dimethylplieiiol and ethyl. methylacetoacetate and its 6-nitro and 6-chloro derivatives were hydrolyzed and methylated to a,P-dimethyl(2,4-dimethyl-6-methoxyphenyl)-acrylic acid, 01,0-dimethyl - (2,4- dimethyl - 3 -nitro - 6 -methoxyphenyl)-acrylic acid and a,P-dimethyl-(2,4-dimethyl-3-chloro-6-methoxyphenyl)-acrylic acid. 3. Several of these acrylic acids formed alkaloidal salts which were oils, others crystallline salts which dissociated readily. Success a t tended only the resolution of a,P-dimethyl-p(2,4-dimethyl*6-methoxyphenyl) -acrylic acid. Its half-life was seventy-four minutes in n-butanol at 44O and therefore much less than that of a-
methyl-~-chloro-~-(2,4-dirnethyl-3-chloro-6-methoxypheny1)-acrylicacid (one hundred afid seventythree minutes). Thus it would appear that in this series of ar);lacrylic acids, a &methyl has less effect on the stability than a &chlorine atom. 4. A discussion of the geometric structure *about the double bond of these acrylic acids is given. URBANA,ILLINOIS
RECEIVED JANUARY 29, 1945
LABORATORIES OF MER- & Co., INC.]
Some New Aminopyrazines and their Sulfanilamide Derivatives BY JOHN WEIJLARD,MAXTISHLER AND A. E. ERICKSON It has been established tbat the introduction of methyl groups into the heteracydic system of N' heterocyclic derivatives of sulfanilamides affects chemotherapeutic activity. In some instances the methyl derivatives are superior to the parent drug.* The therapeutic importance of 2-sulfanilamidopyrazine (sulfapyrazine) indicates the necessity for the study of the substituted pyrazine(1) For a recent review of this subject see E. H. Northey, I d . En#. Chrm.. 36, 829 (1943). (2) Ellingson, THISJ O U R N A L , 6S, 2524 (1941); Raiziss, Clemence and Freifelder, j b i d . , 63, 2739 (1941);Sansville and Spoerri, i b i d . , 63, 3153 (1941); Hamburger, Rettgsegger, Brookens and Eakin, A m . 1, M c d Sci., 204, 186 (1942).
sulfonamides as effective chemotherapeutic agents. A search of the literature for the requisite alkyl and aryl substituted aminopyrazines revealed that only one such derivative, 2-amino-3,6-dGnethylpyrazine (prepared in poor yields by aminating 3,6-dimethylpyrazine with sodamidea)seems to be known. Moreover, the recorded methods for preparing aminopyrazine itself are laborious and the yields poor.4 These processes entail the oxida(.3) C'hichibahin aud Shukina, j. Russ Phys -Chem. SOC, 88, 1189 (1930). Joiner and Spoerri, THISJOURNAL, 63, 1929 (1941). ( 4 ) Gabriel and Sonn, Bcr 40, 4859 (1907), Hall and Spoerri. THlS J O U R N A L , 62, 664 (1940) ~
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803
tion of quinoxaline to pyrazine-2,3-dicarboxylic carboxylic acids which are readily decarboxylated acid and conversion of the latter to aminopyra- to the aminopyrazines. Lumazine is very slowly zine by a series of steps involving a Hofmann degradation. We have developed a simple and probably gem era1 method for preparing 5- and 6-alkyl or aryl substituted aminopyrazines as well as the parent amine whereby the amines are formed directly on heating the corresponding lumazines6 with sulfuric acid. Aminopyrazine (I) is obtained from lumazine in 79% yield; however, substituted aminopyrazines are formed in lower yields from attacked by alkali a t 100-105°.8 At this temperathe corresponding lumazines. The substituted ture a mixture of lumazine in 20% sodium hyaminopyrazines prepared by this simple proce- droxide is only slightly hydrolyzed in five hours dure include 2-arnino-5,6-dirnethylpyrazine(11), but is converted in good yields to the amino acid 2-amino-5,d-diphenylpyrazine (111),2-amino-5 (or in 72 to 96 hours. The optimum yield of 2-amino6)-phenylpyrazine (IV), and 2-amino-6-methyl- pyrazine-3-carboxylic acid is obtained when a solution of lumazine and two to three equivalents pyrazine (V). of 12% alkali is heated a t 170' for two hours. Stronger alkali and longer heating times yield some 2-hydroxypyrazine-3-carboxylic acid, the sole product when lumazine is heated with four equivalents of alkali a t 170' for twenty-four hours. Under these conditions 2-aminopyrazineI, Ri, Rz H 11, RI, Rz CHa 111, RI, Rz = CsHs IV, R1 = Ce.Ha; RP =a H 3-carboxylic acid is also converted to the hydroxy acid. The latter is readily decarboxylated V, R1 = CHg; Rz = H to hydroxypyrazine by heating in an appropriate The concentration of the sulfuric acid is im- solvent at about 200'. It is interesting to note portant in cleavage of lumazines. For lumazine that although substituted hydroxypyrazines have itself, 100% sulfuric acid is best, whereas with been ~ r e p a r e d ,the ~ parent compound, hydroxymethyl and phenyl derivatives 80% sulfuric acid pyrazine, has not been described. gives optimum yields. The reaction is carried In contrast to lumazine, the substituted lumaout by heating the lumazines with sulfuric acid zines under the alkaline cleavage conditions do above 190'. The high yield of aminopyrazine not form the hydroxy acids. The substituted from lurnazine by heating with 100% sulfuric amino acids, unlike 2-aminopyrazine-3-carboxylic acid a t 240' for fifteen minutes is striking and acid, are stable to strong alkali a t elevated tembears witness to the resistance ef the pyrazine peratures. The substituted amino acids are de-' nucleus to substitution reactions. carboxylated conveniently by heating with 80% As methyllumazine, prepared from methyl sulfuric acid. glyoxal and 4,5-diamin0-2,6-dihydroxypyrimidine, The sulfanilamidopyrazines were prepared by is either 6- or 7-rnethyllumazine or a mixture of the reaction of the aminopyrazines and acetylthe two,6 the aminomethylpyrazine derived from sulfanilyl chloride in the presence of pyridine it mqst be either 2-amino-5- or -6-rnethylpyra- followed by acid hydrolysis of the acetyl derivazine or a mixture. The product obtained by us tives thus formed. 2-Sulfanilapido-5,6-diphenylafter recrystallization was essentially a pure com- pyrazine is particularly interesting because of its pound. A phase-solubility study indicated that unusual solubility in organic solvents. The the purified amine was a t least 97% pure.6 To chemotherapeutic activities of these compounds establish the structure of the amine, we synthe-' are under investigation in the Merck Institute sized 2-amino-5-methylpyrazine from 2-carboxyl- for Therapeutic Research and will be reported .?-methylpyrazine' by conversion to the amide later. and Hofmann degradation of the latter. As the Experimental resulting 2-amino-5-methylpyrazineis different Lumazines.-The method for preparing the lumazines from the compound obtained by cleaving monomethyllurnazine, the amine in question must be consistsof allowing the appropriate a-dicarbonyl compound 2-amino-6-rnethylpyrazine(V) . ( 8 ) The possibility of converting lumazine to aminopyrazine by The lumazines are also cleaved by alkalies. The hydrolysis under both acid and alkaline conditions was disclosed to discussed with Drs. C. E. Bills, R. C. Ellingson and F. G . Mcproducts are derivatives of 2-aminopyrazine-3- and Donald of Mead, Johnson & Co., who a t a later time revealed t o us (5) The preparation of lumazines has been investigated by (a) Kuhn and Cook, Bcr., 70,761 (1937), (b) Ganapati, J . Indian Cham. SOC.,14, 627 (1937). (6) We are indebted t o Dr. N. R Trenner of the Research Laboratories of Merck & Co., Inc., for carrying out this study. (7) Gabriel a d Pinkus. Bcr.. 28, 2206 (1893); Stoehr, J . prokt. C h m , 4T, 480 (1896).
(private communication) that they had succeeded in developing the a?kJine hydrolysis of lumazine a t elevated temperatures t o produce 2-aminopyrazine-3-carboxylic acid in commercially satisfactory yields. (9) Japp and Knox, J . Chcm. Soc., 87, 701 (1905); McCombie and Parry, ibid., 96,584 (1909); Ingram. ibid., 180,692 (1927): Totaaad E l d d c l d , J . &g. Chem.. 1, 313 (1942).
804
JOHN
C ~ E I J L A R D , MAXTISHLER AND A. E. ERICKSON
Vol. 67
crude acid in 120 cc. of boiling water, adjusting the PH t o 2.5 with hydrochloric acid, decojorizing, and cooling; yield 1.6 g., m. p . with dcc. 201*.1* The product gives a winered color when treated with a solution of ferric chloride. Anal. Calcd. for C5H5O2K3: C,' 43.13; H , 3.61; N, 30.23. Found: C, 43.26; H, 3.61; N, 29.86. 2-Amino-6-methylpyrazine-3-carboxyIic Acid.-A mixture of 18.7 g. of monomethyllurnazine and a solution of 16 g. of sodium hydroxide in 95 cc. of water was heated at 170172" for twenty hours. Thesolution was cooled to 80" and acidified with hydrochloric acid to fiH 2.5. After cooling to 2 O , the product was filtered, washed with ice water and dried a t 80". The average yield of several such runs was 4.7 g. (31.4%) melting at 205". When the crude acid was purified as outlined above, the product melted with dec. a t 211-212'. Anal. Calcd. for C&O&$: C, 47.05; H,-4.60; N, 27.45. Found: C, 46.67; H, 4.47; N, 27.42. 2-Amino-5,6-diphenylpyrazine-3-carboxylicAcid.-Three granis of crude diphenyllumazine was added t o a solution of 6 g. of sodium hydroxide in 30 cc. of water, and the mixturc was boiled under reflux for thirty-five hours. An oily mass separated which solidified on cooling. The upper layer was decanted and the lower was washed with ice watcr and dried in vacuo. The product (crude sodium salt) was dissolved in 30 cc. of warm water, and the amino acid was precipitated with barium chloride solution. The barium salt (2.57 g.) was suspended in 50 cc. of water, 10 cc. of lOy0 hydrochloric acid was added and the mixture was heated to 80'. About 200 cc. of methanol was added to effect solution. The hot solution was filtered, diluted with four volumes of water, and the precipitated fine crystals were collected, washed and dried; yield 1.50 g.; m. p. 188" dec The material was dissolved in ethyl ether, and the solution was filtered and concentrated to a small volume. The product crystallized out an adding petroleum ethcr. The product (m. p. 189" with dec.) gives a winered ferric chloride test. Anal. Calcd. for Cl7H1302N8: C, 70.07; H, 4.50; N , (d) 6 or 7-Monomethyllumazine.-To a solution of 87 14.44. Found: C, 69.90; H , 4.77; N, 11.25. g. ( 1 mole) of isonitrosoacctotic i n 3 iitcrs of water was 2-Amino-5,6-dimethylpyrazine-3-carboxylic Acid.-A added 250 cc. of 5Uy0 sulfuric acid, anti the inisture was 1)oilcd uiider reflux for fifteen minutes. After adding to mixture of 2.7 g. of crude 6,7-diinethyllumazine and a soluthe hot solution 106.5 g. (0.75 niolcj of 4,5-diaiiiin0-2,& tion of 2.7 g. of sodium hydroxide in 25 cc. of water was di~iydro~yi)yriiiiidiiic, the mixture was boiled undci re- heated a t 170-175" for twenty hours. The solution was flux for thirty iiiiuutes, filtered, and cooled to 2". Thc acidified with hydrochloric acid to pH 2.5 and cooled to 2". The crystals were collected, washed with ice water and collected product \vas washed with water aiid dried at 85', dried a t 80"; yield 2.15 g. (91.5%); m . p. with dec. 208yield 104 g. (77.(3y0). Xloii~iietCylluiiiazinewas also prepared by the recorded 209'. A pure sample was prepared by dissolving 0.40 g. of proccduresa yieldiiig a product identical with that obtained crude acid in 65 cc. of boiling water containing a little above with respect to physical properties and behavior on cleavage. In each case the product was difficult to re- hydrochloric acid, chilling the clear solution, collecting the crystallize because of the tendency to form gels. The crystals, etc.; yield 0.30 g.; ni. p . 209-210" with dec. A mixture with the above monomethyl compound melted crude product was used with satisfactory results. a t 192' with dec The product gave a wine-red ferric ( e ) 6- or 7-Phenyllumazine.11 To a warm solution of chloride test. .57 g. of 4,5-diainino-2,6-dihydroxypyrimidine in 750 cc. of Anal. Calcd. for C,H902N3: C, 50.29; H, 5.42; N, water and 150 cc. of concentrated ammonia was added 57 25.15. Found: C, 50.25: H , 5.18; N, 25.60. g. of phcriylglyoxal. The mixture was refluxed for one hour, cooled, and acidified with acetic acid. The product 2-Aminopyrazine.-(a) To 50 cc. of preheated 1 0 0 ~ sulo was scparated and washed with alcohol. The yield of pale furic acid (prepared from 95% sulfuric acid and oleum) yellow product was 72.5 g. (71%); m. p. above 300". was added 5 g. of hydrated (12Q/,water) crude lumazine A n d . Calcd. for CI*HsN402: C, 60.01; H, 3.36. and the mixture was held at 240-245" for fifteen minutes. To the cooled reaction mixture was added 200 g. of ice Found: C , 60.11;. H,.3.54. followed by excess 30% sodium hydroxide. The strongly 2-Aminopyrazine-3-carboxylic Acid.-A solution of hydrated luniazine, corresponding to 20 g. of anhydrous alkaline solution was extracted with ether and the ether material, in 80 cc. of water containing 11 g. of sodium hy- extracts evaporated t o dryness; yield 2.01 g. of material droxide, was heated in a bomb for two hours a t 170". The (79.1%); m. p. 118-120". A mixed melting point with reaction mixture was acidulated with hydrochloric acid (pH 2-aminopyrazine made by the Hall and Spoerri methodl showed no depression. 2.5.j. chilled to 2" and the product collected and washed Anal. Calcd. for CaHsNa: C, 50.50; H, 5.30; N, with ice water; yield 15.85 g . , 93.5%; m. p. 198'. The compound was purified by dissolving 2 g. of the 44.20. Found: C, 50.72; H, 5.24; N,43.83. (b) Twenty-five grams of 2-aminopyrazine-3-carboxylic (10) Bogert and Davidson, THISJOUXNAL. 56, 1668 (1933). acid was mixed with 75 cc. of carbitol acetate and boiled
to react with 4,5-diamiiio-2,6-dihydrosypyrimidine. As oiir procedurcs differ froiii tliosc recordcd6 and result. in txttcr yields, oiir mctliods arc ticscribeti. 4,5-1?ianiino2.ti-tliliydrosyp~~i.il:ljriinc.\va> [Jrq):LrCd accoi-diiig to the T)rr,cr(lureof Ihgei-t aiitl 1hviilso:i."' graiiii of glyosal sodium bi\,a) Lumazine.----l'\v~iit~ suliitv \\.a\ tliswlved in 400 cc. of water, 20 cc. of concd. aiiiitioiii.i \vas added, follonul 10 g . of 4,5-diamino-2,6tlih~droxypq-riiiiitlinc. 'l'lic iiiixtiire was licatetl to ! W 0 for five minutes. The hot solutioii was trcatcd witli charcoal, iiltcred and chillctl. Tlii crurlc iiiaterial coiitaiiiiiig 12% Ivater weighed 11.4 g . ( S , O " / b yield). This protiuct was yui'licientlypure for tlic clrnvage experinleiit.;, Imt to obtaiii 311analytically pure saiiiple it was iieccssary to crystallize twice in water aiid dry at 100" (1 m n i . ) . This purificrl liiiiiazinc melted a t 84% :3-L\)', Anill. Calctl. for CaHiOrS4: C , 43.8:): 11, 2.48; N, :.tfj. Found: C , 49.76; H, 4.35; N, 29.19. ( c j 6,7-Diphenyll~mazine.~~--:I mixture of 14.2 g. 21.0 g. (0.1 mole) of 4,5-tliamiiio-2,G-tfihydroxypyrimidine, (0.1 riiolej of bemil, 1 liter oi water, 1 liter of alcohol and 100 cc. of coiiceiitrated aiiinionia was heated a t 85-90' for me-half hour aiid filtered while hot. After cooling a t 2" for forty-eight hours, the product was collected, washed w i t h i x cvatcr, and thc:~alcohol. The product weighed 2U.2 g . ((i4.5y01arid iiieltcd a t 315-322'. After dissolviiig i i i dilute aiiiiiioiiia aiitl precipitating witli acetic acid, t h e 1iieltj:ig p o i i i t reiiiaiiietl uiichaiiged.
( 1 1 ) The preparation of this compound, the corresponding aminopyrazine and the sulfanilamide derivative of the latter were carried out by Dr 1; Wolf of the Research Laboratories of XIerck & C o , 1 ne
(12) The melting points in all cases were carried out according to U. S. E'. If a faster rate of heating is employed, much higher melting point* arc o1,tainrd; 210' was recorrtrri by Gabriel and S o n n . '
May, 1945
SOME NEWAMINOPYRAZINES AND THEIR SULFANILAMIDE DERIVATIVES
805
under reflux for fifteen minutes. The hot reaction mixture stirring, the mixture was heated as rapidly as the frothing was filtered after adding a little charcoal, $luted with 2Z5 permitted t o 180' and maintained at this temperature for cc. of petroleum ether and chilled t o 0 . T h e crystals ten minutes. The hot solution was poured onto ice and were collected and washed with petroleum ether; yield, made alkaline by the addition of 30% caustic solution. 14.0 g., 82.0%; m. p. 118-120'. The mixture was extracted with ether and the combined ether extracts, after drying over anhydrous sodium sulfate, Anal. Found: C, 50.61; H, 5.32; N, 44.29. 2-Amino-5,6-dimethylpyrazine.-( a) Eight grams of were concentrated t o dryness. The residue, 6.7 g. (76.1%) was essentially pure product (m. p. 124-126'). A sample crude dimethyllumazine was mixed with 120 cc. of 80% sulfuric acid, and the mixture was boiled under reflux at for analysis was recrystallized from ether-petroleum ether. 195-200' for seventy-five minutes. The reaction mixture A sample mixed with (a) melted a t 124-125'. Anal. Found: C, 55.30; H , 6.59; N, 38.91. was worked up as described above; 0.96 g. (18.9%) of product was obtained. 2-Amino-S-methylpyrazine.-A mixture of 5.4 g. of 5This crude product was purified by dissolving 0.25 g. methylpyrazine-2-carboxylicacid, 15 cc. of methanol, 1 g. 111 5 cc. of hot benzene, adding a few drops of petroleum of anhydrous sodium sulfate and 0.4 cc. of concentrated ether and chilling a t 0'. The crystals were collected and sulfuric acid was boiled under r d u x for six hours. The rewashed with petroleurh ethdr; yield 0.15 g., m. p, 14!3-144'. action mixture was treated with charcoal and filtered. The The product was found t o be appreciably volatile zn vacuo alcoholic solution of the ester was chilled in ice, saturated at 65". with anhydrous ammonia and then chilled a t 2' overnight. Anal. Calcd. for CsHoNs: C, 58.48; H, 7.38; N, 34.14. Three volumes of cold ether was added whereby the product separated. The yield of crude 2carboxamido-5Found: C, 58.20; H, 7.15; N, 34.55. (b) A mixture of 2.15 g. of crude 2-amino-5,6-dimethyl- methylpyrazine was 4.85 g. (89.270); m. p. 210-211'. To a cold solution of potassium hypochlorite prepared pyrazine-3-carboxylic acid in 20 cc. of 80% sulfuric acid, from' 13.3 g. of potassium hydfixide, 24 cc. of water, 24 g. was refluxed for ten minutes a t about 200'. The reaction mixture was worked up and the product purified as de- of ice and 4.23 g, of chlorine was added 60 g. of ice and 8.1 scribed 2bove under (a); yield 1.48 g.; (93.773; m. p. g. of crude 2-carboxamido-5-methylpyrazine.The mix140-144 A mixed melting point with the product ob- ture was agitated about twenty minutes a t Oo, allowed t o warm up to room temperature gradually, then heated on tained under (a) showed no depression. the steam-bath forty-five minutes. After cooling, 20 g. Anal. Found: C, 58.26; H , 7.23; N, 33.80. of sodium hydroxide was added, and the solution was ex2-Amino-S,&diphenylpyrazine.+a) Crude diphenyl- tracted with ether. The ether extracts were concentrated lumazine (15 g.) in 225 cc. of 80% sulfuric acid was boiled to dryness. The residue of bright yellow crystals weighed under reflux for thirty minutes at 195-200'. T o the cooled 4.37 g. (67.8%) ; m. p. 116-118'. A mixture with 2-aminoreaction mixture was added 1500 g. of ice followed by 700 6-methylpyrazine melted at 62-70''. cc. of 30% sodium hydroxide solution. The insoluble Anal. Calcd. for CbH7Na: C, 55.00; H , 6.47; N, 38.53. compound was filtered off, washed several times with 15% sodium hydroxide, then water until free from alkali, and Found: C, 54.94; H, 6.20; N, 38.45. 2-Hydroxypyrazine-3-carboxylicAcid.-( a ) Two grams dried in vacuo; yield 2.40 g., 21.9%; m..p. 224-226'. acid was dissolved in 20 After one crystallization from ether, the white compound of 2-aminopyrazine-3-carboxylic cc. of 20% sodium hydroxide solution and the mixture was melted a t 227-228'. Anal. Calcd. for ClsHisNa: C, 77.70; H, 5.30; N, heated in a steel bomb a t 170' for twenty hours. The reaction mixture was diluted with 50 cc. of water and acidu17.00. Found: C, 77.84; H, 5.15; N, 16.67. with hydrochloric acid to a PH of 2.5 to 3. The crys(b) One-half gram of crude 2-amino-5,6-diphenylpyra- lated zine-3-carboxylic acid was added to 10 cc. of 80% sulfuric tals were collected, washed with ice-water and dried; yield 1.62 g. (81%); m. p. 218-220'. acid and the mixture was refluxed for thirty minutes. A sample for analysis was prepared by dissolving the The reaction mixture was worked up as under (a) ; yield crude acid in a solution of sodium bicarbonate in water, 0.125 g. (30.0%); in. p. 225-227'. After one crystallization from ether, the compound melted at 227-228". A decolorizing, and reprecipitating with acid. The white melted at 218-220' and gave a wine-red color mixed melting point determination with the product ob- compound when treated with ferric chloride solution. tained under (a) showed no depression., Anal. Calcd. for CbH40sNl: C, 42.84; H , 2.88; N, Anal. Found: C , 77.68; H, 5.40; N, 17.01. 2-Amin0-5( Or 6)-phenylpyrazine.-A mixture of 60 ml. 20.00. Found: C, 42.64; H, 3.21; N, 20.40. (b) To a solution of 122 g. of sodium hydroxide in 600 cc. of 80% sulfuric acid and 4.8 r;. of phenyllumazine was heated a t 217-222" for fifteen minutes. After cooling and of water was added 125 g. of lumazine, and the mixture diluting with ice water, the solution was made alkaline was heated a t 170' for twenty-four hours in a bomb. The with ammonia and extracted with ether. The combined reaction mixture was worked up and purified as under (a) ; ether extracts were dried over anhydrous sodium sulfate yield 96.4 g., 91%; m. p. 218-220'. and evaporated to dryness. The residue (0.5 g., 14.50/0) Anal. Found: C , 42.90; H, 2.89; N, 20.29. was recrystallized from water as lustrous white platelets, 2-Hydroxypyrazine.-Five grams of crude 2-hydroxym. p. 13C-13lo. pyrazine-3-carboxylic acid, obtained under (b), was mixed Anal. Calcd. for CIOHONa: C, 70.16; H, 5.30. Found: with 15 cc. of carbitol acetate and boiled under reflux for C, 70.18; H , 5.18. ten minutes. After cooling, 50 cc. of petroleum ether w& 2-Amino+methylpyrazine.-(s) Ten grams of crude added, the crystals were collected and washed with petrohydrated (8% water) monomethyilumazine was ' mixed leumether; yield3.09g., 90.1%; rn.p. 181-182°. The crude material was extracted in a Soxhlet extractor with 200 cc. of SOPJO sulfuric acid, and the mixture was T o the with benzene for five hours, and the crystals removed from boiled under reflux for two hours at 195-200'. cooled reaction mixture was added 1200 g. of ice followed the benzene solution a t room temperature; yield 2.5 g.; The product was dissolved in hot alcoby 800 cc. of 30% sodium hydroxide solution and200 g. of m. p. 186-187'. ammonium sulfate. The alkaline solution was extracted hol, the solution was decolorized, filtered and chilled to 0'. with ether and'the combined ether extracts were concen- The brilliant yellow needles were collected on a filter and trated t o dryness; yield 0.34 g. (6.2%) of crude product. washed with ether;, yield about 90%; m. p. 187-188'. After one crystallization in ether-petroleum ether, the Anel. Calcd. for C4H4QNz: C, 50.00; H , 4.17; N , vellow comDound melted at 1'24-125'. 29.17. Found: C, 50.15; H, 4.44; N, 29.30. . A w l . dalcd. for C*,Na: C, 55.00; H, 6.47; N,38.53. Sulfanilamidopyrazines: Example.-Two grams of 2Found: C, 55.06; H. 6.52; N, 38.27. arnino-5,8-dimethylpyrazinewas dissolved in 25 cg. of pyri(b) Crude 2-amino-6-methylpyrazihe-3-carboxylic acid dine. To the cooled solution was added 4.2 g. of acetyl(12.5 9.) was added t o 37.5 cc. of 80% sulfuric acid. While sulfanilyl chloride in small portions with stirring a t 5 t o 10".
.
a
RICHARDT. ARNOLDAND NEWMAN BORTNICK Over-all yield, Compounda
%
TABLE I -
.
-.
XI. p.. *C.b
Forrnulrr
C
Vol. 67
~ .4nalyses, 70---Calcd.------? 7 -Found---JI N C H
N
2-S-5,6-Dimethylpyrazine 80 261.5-202 Cl2HI4O2S4S 51,76 5.07 2 0 . 1 6 51.62 4 . 9 5 2O.:i1 2-NcAcetylS-5,6dirnethylpyrazine 233 -234 CirHi&N4S '/?H& 5 1 . 0 3 t5.20 1 7 . 0 2 51.20 4 . 9 7 17.38 2-S-5,6-Diphenylpyrazinec 41 115 C=HtsO&,S 1IZO 02 %3 4 . 7 9 1 3 . 3 3 02 94 5 . 0 1 13.50 2-N4-Acetyl-S-5,6diphenylpyrazine 194.5-195 CuHmOsN4S 64.83 1 . 5 4 12.61 6 4 . 9 0 4.22 12.56 2-SG-Methylp yrazine 68 258 -259 CiIHlz02X'rS 4 9 96 4 . 6 8 31.21 50.16 4 . 7 1 21 36 2-N4-Acetyl-S-6-rnethylpyrazined 239 -239.5 CI~HI,O&S + I/&O 49.40 4 . 7 9 1 7 . 7 7 1 9 . X 4 . 7 6 17.85 2-S-5-Methylpyrazine 70 237.5-238.5 CIIHI~OZX~S 49.96 4 . 5 8 21.21 90.20 4 . 5 7 21.31 2-N4-Acetyl-S-5-methylpyrazined 240 -241 CisHiaOaN4S 50.134 4.61 18.30 51.16 4.97 18.60 2-S-5- or 6-phenylpyrazine 80 270 -271 ClsH1402N4S 58.88 4 . 3 2 17.17 58.82 4 . 7 3 17.16 2-N4-Acetyl-S5- or 6phenylpyrazine 237 -240 C ~ ~ H I ~ O ~ N ~ S 58 68 4.38 57.95 4.66 S = sulfanilamido. All m. 1). corrected. E This sulfa drug dissolves in ether, alcohols, bcnzeiie and chloroforrn. * Mixed m. p. between 2-N4-acetyl-S-6-niethylpyrazine and 2-N4-acetyl-S-5-met1iylpyraziiie, 210 '.
+
+
The mixtbre was held at 40-50' for two hours and allowed providing 1Ilicroallalyses is gratefully acknowlto stand overnight a t room temperature. The greater part edged. of tPle pyridine was, distilled off in wucuo, and the residue SUII.llUary was diluted with 100 cc. of water. The crystalline product was filtered off, washed with water and dried; yield 4.22 Improved ltptho& for preparing lumazine and g., 81.1%. Four grams of the crude acetyl compound was hydro- derivatives substituted in the 6,7-positions have lyzed by boiling with a mixture of 30 cc. of alcohol and been described. A degradation reaction for con15 cc. of concentrated hydrochloric acid under refIux verting lurnazirie and substituted Iumaziiies to for one hour. The mixture was diluted with 100 CC. of amillopyrazines is recorded which has been utiwater and 50 cc. of concentrated ammonia water was lized for the rapid and convenient preparation of added in order t o effect solution. After decolorizing with a suitable charcoal, the solution wBs with acetic 2-aniinopyrazine and 2-aminopyrazines substiacid, the crystals were collected, washed thoroughly and tuted in 5 and 6 positions. On alkaline hydrolysis dried; yield 3.00 g. of 2-sulfanilarnido-5,6-dimethylpyra- the lumazines are converted to the corresponding zine, 86.455. 3-aminopyrazine-3-carboxylicacids which can be The other compounds were obtained in a similar manner. to the 2-ami110pyrazines. In some cases it was necessaiy t o crystallize the compounds vigorous alkaline hydrolysis of lumazine and of from solvents.
Acbowledgment.-We are indebted to Drs, R. T. Major and J. R. Stevens for their interest and valuable suggestions, and to Mr. J. P, Messerly for technical assistance on some of the experiments. Thepid of Messrs. D. F. Hayman, H. Clark, R. N. Boos and Mrs. E. H. Meiss in
2-aminopyrazine-3-carboxylic acid yields 2-hydrox~pyrazme-3-carboxylicacid. From the new aminoPFazines, the CorresPonding new sulfanilamide compounds and their acetyl derivatives have been Prepared, ~ H W A Y N. ,
J.
RECEIVED FEBRUARY 13, 1945
[CoNTRIBUTION FROM THE SCHOOL OF CHEMISTRY OF THE UNIVERSITY OF MINNESOTA]
Studies in the Veratrole Series BY RICHARD T. ARNOLD AXD NEWNZAN BORTNICK~V~
Disabstituted veratrole derivatives of type I are not readily available, and in the past these have been obtained by the degradation of certain Y
I
I1 Newman d, Bortnick
(1) A&st=racted from the Ph.D. thesis of which was accepted by the Graduate F a u l t y in Februnry, 1944. ( 2 ) Sharp and D o h m e Fellow, 1942-1944.
alkaloids3 or by tedious indirect synthetic methods. Direct nuclear substitution U S U ~ Ygives rise to the exclusive formation of compounds related to II.4 Carbbxyl groups often undergo r e p l a m e n t during aromatic substitution reactions when they occupy a position ortho or pars to an alkoxy1 group. On the contrary, ester groups are not eliminated unless they are converted to carboxyl during the course of the reaction. By applica(3) Hawortb, Perkin and Stevens, J . Chcm. Soc.. 1784 (1926) (4) Arnold and Bordwell, Tms JOURNAL, 64, 2983 (1942).
